Calibration method for the prospective calibration of measuring equipment

ABSTRACT

A method for operating measuring equipment for detecting at least one analyte in a bodily fluid by means of at least one continuously measuring blood glucose sensor. At least one calibration method is carried out for the prospective calibration of the measuring equipment. At least three calibration points are detected in the calibration method, wherein each calibration point comprises at least one measurement signal from the measuring equipment and at least one reference value of an associated reference measurement. A plurality of possible slopes are established between the calibration points. At least one robust estimation method, more particularly using a formation of at least one median, is used to determine at least one probable slope from the plurality of possible slopes. Furthermore, at least one measurement is carried out. During the measurement and using the probable slope, a concentration of the analyte in the bodily fluid is deduced from at least one measurement signal from the measuring equipment and the probable slope.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/405,815, filed Feb. 27, 2012, which is a continuation ofPCT/EP2010/062474, filed Aug. 26, 2010, which claims priority toEP09168797.0, filed Aug. 27, 2009, both of which are hereby incorporatedby reference in their entireties.

BACKGROUND

The invention relates to a method for operating measuring equipment fordetecting at least one analyte in a bodily fluid, a computer programwith program code for carrying out the method, and to measuringequipment for detecting at least one analyte in a bodily fluid, which isdesigned to carry out the method according to the invention. Suchmethods and devices are used, in particular, in medical technology inorder to monitor, either continuously or discontinuously, one or moreanalytes in bodily fluids such as blood, interstitial fluid or othertypes of bodily fluid, for example at home or in care homes orhospitals. In particular, the method can be used for operating measuringequipment with at least one continuously measuring blood glucose sensor.Such sensors, by means of which it is possible to carry out so-calledcontinuous monitoring, are generally implanted into fatty tissue orinterstitial tissue of a user for a number of days in order to thengenerate measurement signals, for example at regular or irregular timeintervals, from which the concentration of the at least one analyte canbe deduced. The at least one analyte can, in particular, be glucose, forexample blood glucose. However, in general, applications other than theaforementioned applications and the applications described below arealso possible.

Since these are implanted sensors, the systems must be calibrated usingalready established measurement methods. Treating the error of thereference system and establishing the calibration data “in the field”,i.e., without a norm, are therefore a particular challenge for thesesystems.

Measuring equipment for detecting at least one analyte in a bodily fluidis generally based on one or more physical and/or chemical measurementprinciples, by means of which one or more measurement signals aregenerated accordingly. By way of example, these measurement principlesmay be electrochemical measurement principles, by means of which one ormore analyte concentrations can be detected. Such electrochemicalmeasurement principles are known from the prior art.

However, a problem with such devices lies in the fact that, at first,the measurement signals generally are without physiological meaning. Byway of example, the measurement signals may be simple currents, measuredin, e.g., milliampere or nanoampere. In order to obtain information thatcan be used physiologically from these measurement signals, thesemeasurement signals need to be converted into a corresponding analyteconcentration by means of a suitable conversion prescription. Thisconversion prescription, which may for example be stored in a dataprocessing device, is generally also referred to as calibration.

In order to apply the conversion prescription, characteristic variables(parameters) are generally required. Not all of these can be defined inadvance since the sensor is implanted by the patient and hence themeasurement surroundings are not precisely defined. Therefore it isnecessary to carry out comparison measurements during the measurement sothat the measurement signals can be very accurately converted into theanalyte concentration, with no absolute norm or reference beingavailable.

The concentration of the at least one analyte is determined in advanceduring a comparison measurement by means of one or more referencemethods. In the following text, the disclosure will be made withreference to blood glucose as the analyte. However, alternatively or inaddition thereto, it is possible to determine other types of analytes.By way of example, when determining blood glucose, the blood glucose canbe determined directly by means of a chemical detection method and/or bymeans of another type of reference measurement, the calibration of whichis already known. The measurement signals from the measuring equipmentare then related to the reference values of the reference measurementsfor the calibration. By way of example, these can be measured currentcurves of continuously measuring glucose systems (continuous monitoringsystems), which are related to blood glucose measurements that aremeasured in another way, for example individual measurements using teststrips. This known relationship, which is included in a correspondingcalibration, can then be used to deduce a concentration of the analytein the bodily fluid during future measurements from measurement signalsfrom the measuring equipment. It should be noted here that the referencemeasurements also have a non-negligible measurement error.

H. Passing and W. Bablok: A New Biometrical Procedure for Testing theEquality of Measurements from Two Different Analytical Methods:Application of linear regression procedures for method comparisonstudies in Clinical Chemistry, part I, Journal of Clinical ChemistryClinical Biochemistry, Vol. 21, 1983, pages 709-720, have, in general,disclosed a biometric method for checking the equality of measurementvalues from two analytical methods. Here the use of linear regressionmethods in method comparison studies in clinical chemistry is describedretrospectively.

The prior art has disclosed a multiplicity of calibration methods formeasuring equipment, in particular for glucose measuring equipment.Here, the following text refers in particular to measuring equipmentcomprising at least one continuously measuring sensor, more particularlyat least one continuously measuring blood glucose sensor, without thisrestricting possible further applications.

Many of the known methods for calibration create a correlation betweenthe measurement signal and the glucose profile in the blood usingvarious standard regression methods. By way of example, this can be alinear regression, a fit according to the method of least squares or thelike. An example for such linear regression methods is presented in EP 1154 718 B1. There sampled data from a glucose monitoring device arecalibrated using at least one blood glucose reference read out. Moreparticularly, it proposes calculating calibration factors using a linearregression.

A further method for calculating a relationship between the measurementsignals and the reference values lies in the use of expert systems. Byway of example, these are mentioned in U.S. Pat. No. 6,326,160 B1 or inU.S. Pat. No. 6,233,471. These methods use weighted sums to create acorrelation between a continuously measured current profile and a bloodglucose profile.

US Publication No. 2008/0081977A1 has likewise disclosed a calibrationmodel, which in particular also takes offset times between detecting thereference values and the measurement signals into account.

US Publication No. 2008/0021666 A1 likewise undertakes the plotting ofcalibration data over measured data. A regression method (in this case aleast squares regression) is also undertaken in this document, and thisis used to calculate a slope of a fitted straight line through thecalibration points.

US Publication No. 2006/0281985A1 has disclosed a method for calibratinga biosensor for detecting an analyte. Here, a multiplicity ofmeasurement signals from the biosensor are detected over a period oftime. A median filter is applied to this multiplicity of measurementsignals, and the median value obtained thus is used to establish sensorsensitivity from a comparison with a measured blood analyteconcentration. Here different weightings of the sensitivities can beundertaken for the different phases.

Furthermore, there often is the problem of handling the multiplicity ofdata in the case of real measurements, particularly in the case ofcontinuous measurements that are undertaken over a relatively longperiod of time. Data compression methods, like the ones described in,e.g., U.S. Pat. No. 7,389,133 B1 or US Publication No. 2007/0016127 A1,were developed for this purpose.

However, in terms of practical handling, the presented prior art has amultiplicity of disadvantages and technical challenges. Thus, forexample, most of the described calibration methods do not, or onlyinsufficiently, account for the occurrence of outliers. Thus, forexample, the calibration may yield extraordinary calibration points,i.e., calibration points which are a long way outside of the profile orvalue range that is expected in accordance with the remainingcalibration points, and are colloquially referred to as outliers.Although these can be discarded within the scope of plausibilityanalysis, this can in turn lead to a falsification of the calibration.

Methods for converting the measurement signals into interpretableanalyte concentrations, for example blood glucose values, should ingeneral reproduce the profile of the analyte concentration as preciselyas possible. Moreover, these methods should be robust with respect tooutliers, which are created as a result of random and systematicnegative influences such as temperature, movement of the user (e.g., apatient) or similar negative influences. Nor is the influence of ameasurement error in the reference measurement taken into account. Theknown measurements only insufficiently take account of theserequirements. Here, an essential point in many cases is that themeasurement signal can be strongly dependent on the location and/orpositioning of the actual sensor and, e.g., in the case of implantedsensors, on insertion influences. Hence a calibration in advance, as isconventional in test-strip systems, is generally unavailable.

In order to calibrate the measurement signals from continuouslymeasuring sensors, use is therefore often made of sporadic, e.g., spacedapart by twelve hours, spot measurements, in which the calibration isfor example carried out with respect to one or more reference valuesmeasured by means of test-strip equipment. However, this procedureharbors a number of challenges for the calibration. Thus, for example,although a blood glucose level, as can be measured by spot monitoringsystems, and an interstitial glucose level, as can be measured by e.g.,a continuously measuring, implanted sensor, are strongly correlated,they initially are two different measurement objects. In particular,dead times, which are not necessarily constant, may occur between theblood glucose profile and the interstitial glucose profile. Moreover,the blood glucose values used for the measurement can hardly bemonitored in practice. While normal calibration methods haveprescriptions in respect of the covered concentration range, here thereoften is a dependency on processing the concentration ranges prescribedby the patient. Accordingly, it may be that the concentration range,within which a calibration can be carried out, is comparatively small.Later measurements may be correspondingly imprecise if measurementsignals occur outside of the calibrated range. Furthermore, the numberof available calibration points is severely restricted in practice, andthese calibration points harbor great uncertainty since these aregenerally carried out not by means of reference measurements underlaboratory conditions, but by means of reference measurements usingsimple, everyday blood glucose equipment and under undefined measurementconditions. Likewise, the complete number of calibration points isgenerally only available at the end of the measurement time. However,the user generally wishes to be informed at the earliest opportunity inrespect of the profile of his glucose level.

SUMMARY

The present invention provides a method for operating measuringequipment and corresponding measuring equipment that addresses thedisadvantages of known methods and measuring equipment. In particular, acalibration method that is robust against outliers and referencemeasurement errors is taught, which calibration method allows a reliableevaluation of measurement values even under conditions that areprevalent in practice.

This advantage is achieved by a method, measuring equipment and acomputer program having the features of the independent claims.Advantageous developments of the invention, which can be implementedindividually or in combination, are presented in the dependent patentclaims.

A method for operating measuring equipment for detecting at least oneanalyte in a bodily fluid is proposed in a first aspect of thisdisclosure. As illustrated above, this measuring equipment can moreparticularly detect the analyte by means of at least one continuouslymeasuring blood glucose sensor. However, in principle, use can also bemade of other types of sensors, for example sensors that, alternativelyor in addition thereto, detect other types of analytes, and/ornon-continuously measuring sensors.

In the method, at least one calibration method is carried out for theprospective calibration of the measuring equipment. Here, a prospectivecalibration should be understood to mean the establishment of aconversion prescription, which, in future measurements, allows theconversion of measurement signals from the measuring equipment, forexample from at least one sensor of the measuring equipment, into aconcentration of the analyte in the bodily fluid. However, in additionto at least one prospective calibration, there also is the option ofcarrying out at least one retrospective calibration, in whichmeasurement signals are subsequently reevaluated and reconverted intoanalyte concentrations on the basis of subsequently obtainedinformation; this is explained in more detail below.

At least three calibration points are detected in the calibrationmethod. More than three calibration points can preferably be detected inthis case. By way of example, as will be explained in more detail below,new calibration points can be added iteratively and taken into accountduring the calibration method. Older calibration points may optionallybe discarded or given a lower weighting. Here each calibration pointcontains at least one measurement signal from the measuring equipmentand at least one reference value from an associated referencemeasurement. This means that at one point at least one measurementsignal from the measuring equipment is detected for establishing acalibration point. At least one reference value is detectedsimultaneously or with a time offset that is as small as possible (e.g.,a time offset of no more than 5 minutes, preferably of no more than 1minute) by means of a reference measurement; this reference valuesupplies information in respect of an actually present analyteconcentration in the bodily fluid. The reference value can naturallyalso be afflicted by errors and should accordingly merely represent anas accurate as possible estimate or determination of the actuallypresent analyte concentration in the bodily fluid, which is obtained bythe reference measurement. The reference measurement should accordinglybe carried out by means of at least one method that is known to supplymeasurement results that are as close as possible to the actual presentanalyte concentration. By way of example, this reference measurement cancomprise a blood glucose measurement by means of another method, e.g., aspot measurement, in which a sample of the bodily fluid is examinedonce. By way of example, the reference measurement can comprise ameasurement using handheld equipment. However, alternatively or inaddition thereto, the reference measurement may in principle alsocomprise a laboratory measurement. In the following text, reference ismade in particular to the reference measurement by means of one or moreitems of handheld equipment, more particularly by means of one or moretest strips, for example using an optical and/or electrochemicaldetection method.

The measurement signals and the reference values are combined to formcalibration points. Moreover, the calibration points may comprisefurther information. By way of example, the calibration points can bestored on a data medium, for example on a data medium of a computer of acontrol of the measuring equipment.

In principle, the measurement signals of the calibration points may beraw measurement signals, which were detected by the measuring equipment.However, these measurement signals may alternatively also already be atleast partly processed measurement signals, for example measurementsignals that were detected over a period of time and subsequentlysubjected to data processing, e.g., filtering, averaging, smoothing or alinearization transform. A linearization transform maps a nonlinearrelationship between measurement signals and a concentration of theanalyte onto a linear relationship. The calibration is carried out inthe linearized representation, wherein, in order to represent theconcentration, a transform that is complementary thereto is carried out.The linearization transform reproduces an approximate dependence betweenmeasurement signals and concentrations, which reflects properties of themeasurement system. By way of example, saturation at high concentrationscan reduce the sensitivity of the measuring system with increasingconcentration. A logarithmic dependence between measurement signal andconcentration may be assumed for this range in particular. Alinearization transform transforms the measurement signals of this rangein particular according to this dependence in order (approximately) toobtain a linear relationship between measurement signal andconcentration. The calibration is undertaken using the linearized valuesof the measurement signal in order to be able to carry out theunderlying observation of the possible slopes between measurement pointswithout an error based on a nonlinear relationship. The linearizationtransform corresponds to the inverse function of the relationshipbetween measurement signal and concentration. A complementary transformfor converting the measurement signal into concentration values in turncorresponds to the inverse function of the linearization transform andhence to the relationship between measurement signal and concentrationvalues that emerge from the properties of the system. The linearizationtransform may relate to only one interval of the measurement signal (forexample, an upwardly unbounded interval, which corresponds to asaturation range of the measurement system) or it may relate to theentire range of the measurement signal. Furthermore, the linearizationtransform may be a function that was obtained empirically andempirically reproduces the properties of the measurement system or afunction that maps at least one physical process, e.g., sensorsaturation. Furthermore, the linearization transform can be representedby a polynomial or a spline, or by a series expansion, with theassociated coefficients determining the transform.

Such a transform may also be used to compensate for a temporal change(degeneration) of the sensor. Here, this transform may be carried outindependently of the above-described linearization step. Alternatively,the transforms presented in this section and in the preceding sectioncan be carried out in combination, i.e., a temporal drift andnonlinearity can be carried out in a (common) step using atwo-dimensional transform.

It is also possible to form a median within the scope of dataprocessing. The same also holds true for the reference values. If aplurality of reference values are available, these can also be subjectedto data processing. In general, if such data processing is provided, theprocessed measurement signals and the processed reference values arecombined to form the respective calibration points. Thus, eachcalibration point comprises at least one measurement signal, optionallya processed measurement signal, and at least one reference value,optionally a processed reference value.

Once the at least three calibration points have been detected, aplurality of possible slopes are established between the calibrationpoints. By way of example, if there are three calibration pointspresent, these are 2*3/2=3 slopes. In the case of n calibration points,there are n*(n−1)/2 possible slopes. Here, all calibration points may betaken into account such that all possible slopes are established betweenthe calibration points. However, alternatively it is also possible toignore one or more of the possible slopes in the calibration method suchthat fewer slopes are established than the aforementioned maximum numberof possible slopes. However, in each case at least two slopes should beestablished between calibration points, preferably at least three slopesand particularly preferably more than three slopes. However, referenceis made to the fact that the calibration method may optionally also bestarted at first with only a single calibration point being present. Byway of example, the origin can initially be assumed as a furthercalibration point and it can optionally be discarded at a later time.These two points, i.e., a measured calibration point and an assumedcalibration point, which may, for example, be the origin, can then beused to define a straight line, whose slope and axis intercept (thisnaturally equals 0 if the origin is selected as selected calibrationpoint) can be determined. Alternatively, or in addition thereto, it isalso optionally possible for the calibration to be started at first withtwo calibration points, which define a straight line. The slope a andthe axis intercept b of this straight line can likewise be determined.

At least one robust estimation method is then used to determine at leastone estimator for the slope of the calibration straight line, which isreferred to as a probable slope in the following text, from the possibleslopes between the calibration points established in this way. Here, arobust estimation method is understood to mean a statistical estimationmethod that still supplies stable statistical estimators even ifoutliers occur or even if distribution assumptions are onlyapproximately valid.

In principle, a person skilled in the art is aware of such robustestimation methods, for example from the publication by H. Passing andW. Bablok, mentioned at the outset; however, there they are discussedwithin the scope of a retrospective method comparison. However, therobust estimation methods described therein may, in principle, also beapplied within the scope of these teachings. In the process, it is alsopossible to combine different robust estimation methods. In particular,it is possible to use robust estimation methods that are based on one ormore permutation algorithms and/or one or more sorting algorithms, i.e.,algorithms in which values are ordered according to magnitude. Aparticularly preferred exemplary embodiment of a robust estimationmethod and more particularly of a sorting algorithm is an estimationmethod that uses a formation of at least one median. Accordingly, it isparticularly preferred if the at least one probable slope is determinedfrom the plurality of possible slopes by forming a median. By way ofexample, if n calibration points were determined, and accordinglyn*(n−1)/2 slopes or fewer, however, at least two, preferably three, fouror more slopes, the probable slope can be determined from these possibleslopes as the median of the established slopes.

Here, the median of a series of measurements is a numerical value, forwhich at least half of all observations in the series of measurementsare less than or equal to the median and at least half of allobservations in the series of measurements are greater than or equal tothe median. It follows from this definition that individual outliers donot influence the median. The median is therefore a robust estimator forthe expected value of a random variable. In the case of a number ofpossible slopes {a₁, a₂, . . . a_(n)}, which are sorted according tomagnitude, the value a_((n+1)/2) is typically used as median if n isodd, and the arithmetic mean ½(a_((n/2))+a_((n/2)+1)) is used if n iseven. In principle, as an alternative to using the formation of themedian or in addition thereto, it is also possible to use other robustestimation methods, in particular other robust estimation methods thatare based on one or more permutation algorithms and/or one or moresorting algorithms and/or on other types of robust estimation methods.It is also possible to use a combination of a plurality of differentrobust estimation methods.

Furthermore, at least one measurement is carried out in the proposedmethod. During this measurement and using the probable slope, aconcentration of the analyte in the bodily fluid is deduced from atleast one measurement signal from the measuring equipment and theprobable slope. By way of example, it is possible to assume an offset oran axis intercept for this purpose, which offset or axis intercept canfor example be obtained from an empirical value or which can bearbitrarily assumed, for example to be zero. Alternatively, or inaddition thereto, it is also possible to use a probable axis intercept,which is determined according to the optional method described below.This at least one measurement signal from the measuring equipment usedfor the measurement may have already been used for the calibrationmethod. However, alternatively or additionally, separate measurementsignals may have been recorded during the measurement and these are thenused to deduce the concentration of the analyte in the bodily fluid. Asexplained above, these measurement signals may for example be one ormore currents, which were for example obtained by means of at least oneamperometric sensor of the measuring equipment, for example when usingone or more electrochemical detection methods for detecting glucose inblood, interstitial fluid or similar bodily fluids.

The inference of a concentration of the analyte in the bodily fluid fromthe measurement signal from the measuring equipment can for example bebrought about by inverting the relationship, determined in thecalibration method, between the reference values and the measurementsignals. By way of example, such an inversion is generally possible in asimple fashion by forming an inverse function, at least in the case ofone-to-one functions. Here, the probable slope can for example be usedas so-called sensitivity and can be inverted to form the inversefunction, in order to deduce the concentration of the analyte in thebodily fluid from the at least one measurement signal from the at leastone measurement.

Here, the method can be carried out repeatedly and/or such that the twoaforementioned method steps of the calibration method and the referencemethod are carried out parallel in time, overlapping in time ordistributed in time.

In a particularly advantageous embodiment, furthermore, a plurality ofstraight lines are determined during the calibration method, the slopesof which straight lines correspond to the probable slope andrespectively contain a calibration point. This plurality of straightlines is preferably determined through all calibration points, wherein,however, a smaller number than the maximum available number ofcalibration points can also be used. Overall, this forms a plurality ofparallel lines, which each have the probable slope and run through theplurality of the calibration points. In general, these straight linesintersect the axes, e.g., the y-axis, at different points. The axisintercepts of the straight lines are determined in each case. Here, anaxis intercept should be understood to mean the intersection of thestraight line with the y-axis. However, another variable can also besubsumed by this term, from which variable, if need be with the aid ofthe probable slope, it is also possible to deduce the axis intercept,e.g., the point of intersection with the x-axis. Which axis is thex-axis and which axis is the y-axis in this representation depends onthe type of plot and, in principle, can vary. Thus, by way of example,the blood glucose value or the value of the concentration of the analytein the bodily fluid can be used as x-axis and the value of themeasurement signal from the measuring equipment can be used as y-axis,or vice versa.

Thus the proposed method is preferably used to determine a plurality ofaxis intercepts of the straight lines. At least one robust estimationmethod can subsequently be used to determine at least one probable axisintercept from these axis intercepts. In principle, this may be the samerobust estimation method used in determining the probable slope or inprinciple this may also be another type of robust estimation method.However, the use of a formation of at least one median of the axisintercepts for determining a statistical estimator of the axisintercept, which is referred to as probable axis intercept below, isonce again particularly preferred. However, alternatively or in additionthereto, use can for example in general also be made of otheralgorithms, which are based on one or more permutation algorithms and/orone or more sorting algorithms, from which the formation of a medianmerely constitutes a preferred example.

If the probable axis intercept is determined in this fashion, theprobable axis intercept is used during the measurement in addition tothe probable slope in order to deduce the concentration of the analytein the bodily fluid from the measurement signal from the measuringequipment. The probable axis intercept and the probable slope prescribea uniquely prescribed linear relationship between the analyteconcentrations in the bodily fluid and the measurement signals from themeasuring equipment, which can also be easily inverted. However,reference is made to the fact that the probable axis intercept can alsobe established using a different method than using a robust estimationmethod, for example by a non-robust estimation method, for example by aparametric estimation method. By way of example, there may be simpleaveraging, for example by forming an arithmetic mean, of the axisintercepts and/or another type of straight line, which has the probableslope, through the calibration points may be used.

As illustrated above, the calibration method can more particularly becarried out repeatedly, in particular at different times. In theprocess, after repeating the calibration method, it is, in particular,possible to determine a new probable slope and preferably a new probableaxis intercept. This new probable slope and, preferably, the newprobable axis intercept can then be used in place of the previously usedprobable slope and the previously used probable axis intercept in atleast one subsequent measurement in order once again to deduce theconcentration of the analyte in the bodily fluid from at least onemeasurement signal.

The proposed method can furthermore be combined with known methods.Thus, for example, plausibility analysis can be carried out during thecalibration method. Here, the plausibility analysis is an inspection inwhich values that lie outside a prescribed range are not taken intoaccount. By way of example, the prescribed range may contain empiricalvalues. Thus, unrealistic calibration points and/or unrealistic slopesand/or unrealistic axis intercepts may be discarded in the plausibilityanalysis. The calculation may also be carried out iteratively with anumber of subsets of the calibration points, for example using a“leaving-one-out” method in order to examine the dependence of theprobable slope or of the probable offset on a calibration point.

Furthermore, at least one current calibration quality may be determinedin the proposed method. In principle, a calibration quality should beunderstood to mean at least one indicator that specifies the uncertaintyinflicted on the current calibration, i.e., the uncertainty in thededuction of the concentration of the analyte in the bodily fluid from ameasurement signal when using the current calibration. In particular,the calibration quality may comprise at least one confidence interval,i.e., a standard deviation, for example, or a multiple of the standarddeviation.

The change of the determined slope and of the axis intercept compared tothe preceding calibration can also be used as a test statistic in thiscase as to whether the sensor still has the required sensor properties.By way of example, this is how outliers are identified, with these thenbeing discarded as a calibration result in order to carry out a newcalibration. If the slope of a current calibration differs from theslope of the preceding calibration or from the slopes of the precedingcalibrations by more than a predetermined measure (corresponding to theconfidence interval), the current calibration is discarded and a newcalibration is carried out (i.e., the calibration is repeated).

The method can furthermore be carried out such that a user is,preferably automatically, invited to carry out the calibration method.Here, a distinction can optionally be made between different states,e.g., a recommendation of a further recording of a reference value withthe aid of a conventional blood glucose measurement for improving thecalibration or the mandatory recording of a reference measurement, withthe system being shut down if this calibration is not carried out withina defined period of time. By way of example, this invitation can bebrought about by means of at least one optical and/or acoustic and/orhaptic indication, which invites the user to carry out the calibrationmethod. In particular, this invitation may be brought aboutautomatically, for example by means of a control of the measuringequipment.

In particular, the user can be invited to carry out the calibrationmethod if at least one calibration condition is present, i.e., acondition that makes carrying out the calibration method appear to beexpedient. In particular, this condition may consist of the fact that atleast one current measurement signal lies in a range in which acalibration quality lies below a predetermined quality threshold. By wayof example, this may be as a result of the fact that there are yet to bea sufficient number of calibration points in this region, for examplebecause no measurement signals occurred in this region until now. Thismethod variant takes into account the fact that, contrary to laboratorytrials, analyte concentrations for the calibration cannot be prescribedarbitrarily in practical use in a user, but rather that the calibrationneeds to be carried out using the analyte concentrations actuallyoccurring in the user. By way of example, if the case then occurs that avalue for an analyte concentration is present that has not been presentpreviously, the user can be automatically informed that now is anexpedient time to carry out a calibration method. If a currentcalibration quality is determined, a user can more particularly also beinformed if a current measurement signal is in a region of insufficientcalibration quality. In this case there can, for example, once again bean optical, an acoustic or a haptic indication or signal to the user.This user can also be informed that a measurement of the analyteconcentration is terminated or interrupted automatically, optionallytogether with a note that there is insufficient calibration quality,which may also include an upward or downward deviation from a validregion.

As set forth above, the calibration method can in particular be carriedout repeatedly, for example at regular or irregular intervals, forexample as a result of an invitation by the measuring equipment. Thecalibration information newly obtained in this case, for example a newprobable slope, can then be used for the prospective evaluation offuture measurements. However, alternatively or additionally, there canalso be a retrospective evaluation of measurements already carried out,and so these measurements can be newly evaluated. If the calibrationmethod and/or parts of the aforementioned calibration method are carriedout repeatedly, for example by only newly determining individual newcalibration points, older calibration points can then also be discarded.As explained above, this discarding may either involve completelyignoring these older calibration points or at least a lower weighting ofthese older calibration points. By way of example, older calibrationpoints can be understood to mean calibration points that are older thanat least one prescribed time threshold.

Specific embodiments of the method distinguish between the followingstates:

-   -   (A) Mandatory reference measurement (i.e., calibration), “Must        calibrate”    -   (B) Recommended reference measurement, “Recommend to calibrate”    -   (C) Ready for a reference measurement, “May calibrate” or “Ready        to calibrate” and    -   (D) Good conditions for a reference measurement, “Nice to        calibrate”.    -   (E) Calibration impossible due to bad signal properties, “Must        not calibrate”

In state (A), a display of measurement results is blocked, for example,in order to force the user to undertake a calibration. This state isleft as a result of a successful calibration or reference measurement,and a measurement, including the display of the resultant measurementresults, is made possible, wherein the measurement is based on thesuccessful calibration or reference measurement. State (A) occurs if themost recent calibration/reference measurement dates back longer than apredetermined period of time or if there has yet to be acalibration/reference measurement using the present measurement system.State (A) can furthermore occur if the measurement signal lies in aregion outside of a predetermined, conventional measurement range andindicates a fault, e.g., a contact fault. State (A) does not occur ifthe measurement values lie below a predetermined boundary, with theboundary indicating a critical state of the measurement object, e.g.,hypoglycemia. In the case of measurement values that lie below thisboundary, a different state, in which measurements are carried out anddisplayed, is necessarily called, preferably state (B) or else states(C) and (D). In states (B), (C) and (D) (and also (E)), it is possibleto carry out measurements and display the results thereof. Furthermore,state (A) can be terminated if it lasts for longer than a predeterminedlength; the measurement is preferably terminated in this case.

State (B) displays an invitation to calibrate or the user is informed ofthe necessity of a calibration/reference measurement. State (B) occursif a measurement signal lies outside of the calibration range, i.e.,outside of the reference points of the reference measurement. State (B)preferably occurs if the measurement signal lies outside of a rangeemerging from the calibration range, an adjoining lower tolerance rangeand an adjoining upper tolerance range. The upper tolerance range, whichadjoins the calibration range in the direction of the higher values(i.e., it adjoins the largest value of the reference measurements), hasa width corresponding to a prescribed proportional factor multiplied bythe upper boundary of the calibration range or multiplied by themeasurement signal. The width of the lower tolerance range is preferablyprescribed by an absolute value. Finally, state (B) may be entered if aprescribed period of time has elapsed since the last calibration. Thisperiod of time is shorter than the period of time used in the context ofstate (A). State (B) corresponds to a calibration that still is valid,but the accuracy of which is low, which is why a calibration with ahigher precision should be carried out.

State (C) corresponds to a standard state, which represents the generalreadiness of the device for calibration, for example if a calibrationhas already been carried out. State (C) corresponds to a state in whicha calibration does not necessarily lead to an improvement in themeasurement accuracy, contrary to states (A) and (B).

State (D) is entered if the conditions are particularly favorable for aprecise calibration/reference measurement. This is satisfied if themeasurement results (over a predetermined period of time) fluctuate byless than a predetermined range of fluctuation. In other words, this issatisfied if the dynamics of the measurement results lie below aspecific threshold. The low dynamics or variations indicate a stablestate or a high significance of the reference measurement, wherein thisin turn is linked to high accuracy. In state (D), information isdisplayed that there are good calibration conditions or there is thepossibility of improving the measurement precision.

State (E) is entered if the signal properties make it possible to deducehigh variation or a significant current change in the signal (i.e., themeasurement values), which lies above a predetermined maximum varianceor maximum change. In state (E), the currently validcalibration/reference measurement would be replaced by a less precisevalue as a result of the variation or as a result of the significanttrend (large increase or decrease in the measurement signal over therelevant period of time) because the significant variation/the largeincrease is linked to a large error. It is indicated in state (E) that acalibration should not be carried out. Furthermore, commands toundertake a calibration, to the extent that they nevertheless areentered, are ignored in state (E) and the previous referencemeasurement/calibration is kept. Measurements can be carried out instate (E) and the measurement result is displayed. It is optionallypossible to indicate that the measurement should be repeated(particularly after a calibration outside of the state (E)) and/or thatthe measurement result is not very precise. The current calibration isused in the measurement, with a calibration command entered in state (E)leaving the current calibration unchanged. In state (E), use is made ofa calibration that was carried out prior to the entry into state (E)(i.e., the reference measurement of which calibration was carried outbefore entering state (E)).

States that indicate particularly high dynamics or variation (e.g.,state (E)) and states that indicate particularly low dynamics orvariation (e.g., state (D)) are preferably identified by observing thetemporal or stochastic property of the measurement signal itself. Inthis case, a calculation is made either of a value corresponding to avariance or variation or a calculation is made of a value thatreproduces the first time derivative, or both. Compared to thecorresponding boundary values, this value (these values) serve(s) as abasis for the decision as to whether particularly high/low dynamics orvariation is present. In particular, these values can reproduce themaximum of the dynamics (i.e., the first derivative) or of the variationin the measurement signal. The observation of the measurement signalpreferably relates to a time window of the measurement signal or to thelast N values of the measurement signal, wherein N is a natural number>0(preferably >10, >100 or >1000).

In addition to a start or end state, the method preferably provides forsubstantially only switching between states (A)-(E).

Furthermore, the method can also be modified such that the calibrationpoints and/or components of the calibration points, for example themeasurement signals and/or the reference values, are, eitherindividually or together, subjected to a smoothing method. As analternative to applying a smoothing method during the calibrationmethod, or in addition thereto, the at least one measurement can alsotake place with one or more smoothing methods being carried out. By wayof example, the calibration points and/or the measurement signals can besubjected to at least one smoothing method, more particularly asmoothing method by means of at least one exponential filter. Exemplaryembodiments of such smoothing methods will be explained in more detailbelow.

Furthermore, the method can be developed such that the calibrationpoints and/or components of these calibration points and/or themeasurement signals are subjected to at least one linearization step. Anat least approximately linear relationship between the measurementvalues and the reference values can be produced in this linearizationstep. This method is particularly expedient if a nonlinear relationshipis determined or known to exist between the analyte concentration andthe measurement signals. By way of example, the signal profile of themeasurement signals can exhibit saturation behavior, i.e., have adownward deviation from a linear profile in the case of relatively highvalues of the measurement signals in particular. In this case, theaforementioned linearization step can be undertaken before evaluatingthe calibration points and/or before evaluating the measurement signals.Here, the calibration points and/or the measurement signals can forexample be subjected to a transform, which, as is well known, in turnproduces a linear profile. In the case of saturation behavior, this canfor example be brought about using at least one logarithm, particularlyin the case of measurement values within a prescribed saturation range,in which a partial saturation of the measurement system may be assumed.Examples of linearization steps are illustrated above and will beexplained in more detail below.

Furthermore, a method for operating measuring equipment for detecting atleast one analyte in a bodily fluid is proposed, which method comprisesa data reduction. In principle, this method can be embodied as adevelopment of the above-described method in one or more of theillustrated method variants, and so the features described below may beconsidered to be additional features. However, alternatively the methoddescribed below can also be realized independently, without theabove-described method features of the first aspect of this disclosure.

In this second aspect of a method for operating measuring equipment fordetecting at least one analyte in a bodily fluid, a plurality ofmeasurement signals of the measuring equipment are, in a measurement,detected over a measurement period. By way of example, this measurementperiod may comprise a typical measurement period of a continuouslymeasuring blood glucose sensor, for example of the order of minutes, inwhich, for example, measurement signals are in each case detected insub-minute intervals.

Furthermore, at least one data reduction is carried out. During thisdata reduction, the plurality of measurement value pairs, consisting ofmeasurement signal and measurement time, are reduced to one or a fewmeasurement value pairs. In the process, one or more of the followingdata reduction methods may be applied.

In a first possible data reduction method, at least one robustestimation method is used to determine at least one probable measurementsignal for the measurement time period from the plurality of measurementsignals. The plurality of measurement signals are then replaced by theprobable measurement signal. In respect of the robust estimation method,reference can be made to the above description of robust estimationmethods. Once again, use can also be made of a combination of robustestimation methods. The use of a median is particularly preferred.However, alternatively or additionally, use could in general for examplebe made of other algorithms as well, which are based on one or morepermutation algorithms and/or one or more sorting algorithms, from whichthe formation of a median merely constitutes a preferred example.

Alternatively, or in addition thereto, the data reduction method canalso be carried out in such a way that the measurement signals with theassociated measurement times are combined to form measurement valuepairs. The measurement value pairs can moreover comprise additionalinformation. Furthermore, a plurality of possible slopes between themeasurement value pairs are established, with a probable slope beingestablished from the plurality of possible slopes by means of at leastone robust estimation method. Once again, the statements made above inrespect of the robust estimation method analogously hold true. Inparticular, this robust estimation method can once again be carried outusing at least one median. However, alternatively or additionally, usecould in general for example be made of other algorithms as well, whichare based on one or more permutation algorithms and/or one or moresorting algorithms, from which the formation of a median merelyconstitutes a preferred example.

A plurality of straight lines through the measurement value pairs arethen formed from the plurality of possible slopes. By way of example,this can be brought about by virtue of the fact that straight lines areformed through each point corresponding to a measurement value pair, orat least through a plurality of these points, which straight lines havethe probable slope such that a host of parallel straight lines throughthe points is created. Furthermore, at least one representative time isselected for the measurement time period, for example the middle of thetime interval of the measurement time period. However, in principle, therepresentative time can be selected at any point within the measurementtime period, for example the start point or the end point of themeasurement time period, or any intermediate point. Subsequently, thefunctional values of the aforementioned straight lines, i.e., of all ora plurality of the straight lines, are determined for the representativetime, with at least one probable functional value being established fromthe functional values by means of at least one robust estimation method.Then the plurality of the measurement value pairs are replaced by atleast one representative measurement value pair, which comprises the atleast one probable functional value and the at least one representativetime. In particular, the robust estimation method can once again becarried out using a formation of at least one median. However,alternatively or additionally, use could in general for example be madeof other algorithms as well, which are based on one or more permutationalgorithms and/or one or more sorting algorithms, from which theformation of a median merely constitutes a preferred example. Examplesof the described data reduction method will be explained in more detailbelow.

At least one measure of variation can furthermore be determined duringthe data reduction, in one or both of the described variants, from theplurality of measurement signals, more particularly a standard deviationand/or a measure of the quantile.

Furthermore, it proves possible during the data reduction methods, inparticular during the second variant of the data reduction method, todetermine a trend from the plurality of measurement signals. This trend,which predicts a time profile of the measurement signal on a continuousor ordinal scale, can more particularly be established from the probableslope, which, on its own, already specifies such a trend. For example,the measurement points taken every second can be combined to form asingle measurement point every minute by averaging (optionally withexclusion of outliers).

Furthermore, at least one statement in respect of a signal quality ofthe plurality of measurement signals can be made during the method. Inparticular, this statement in respect of the signal quality can be madeby a comparison between robust estimators of the measurement signals,e.g., once again, of the median (and/or another permutation algorithmand/or sorting algorithm) and/or the measures of the quantile, andparametric estimators of the measurement signals, e.g., of the meanand/or the standard deviation.

In a third aspect, a method for operating measuring equipment fordetecting at least one analyte in a bodily fluid is proposed in turn.The method can once again additionally have the features of theabove-described method variants as per the first and/or second aspect,and so reference can be made to the description above for possiblefurther embodiments of the third aspect described in the following text.However, the third aspect can also be carried out independently of theabove-described embodiment variants.

Concerning the third aspect of these teachings, a calibration ofmeasurement signals from the measuring equipment is carried out againstreference values of associated reference measurements during at leastone calibration method. This can be one or more reference measurements.Reference can be made to the description above in respect of possibleembodiments of the reference measurements. Furthermore, a calibrationstrategy is applied in the method in the third aspect of the invention.In general, a calibration strategy should be understood to mean astrategy for optimizing the calibration, for example for continuouslyimproving the accuracy of the calibration, for example a calibrationquality.

The calibration strategy may comprise one or more of the method stepsdescribed in the following text.

Thus, depending on a current calibration quality emerging, for example,from plausibility analysis, a region of measurement signals from themeasurement region can be restricted, which region can be used for themeasurement. Thus, for example, a region that is covered with sufficientcalibration quality by the previous calibration may be determined as aregion that can be used. By way of example, this may be a region withinwhich reference values are present, optionally with one or moreadditional intervals above or below this region, for example withdimensions of a prescribed percentage. In particular, a user can beinformed if measurement signals are detected outside of a region thatcan be used, for example information can be provided that a lowerboundary was undershot or that an upper boundary was overshot. By way ofexample, this can once again be brought about by an optical, an acousticor a haptic indication.

Alternatively, or in addition thereto, the calibration strategy can alsoinclude an invitation to a user to carry out the calibration methodagain. By way of example, this invitation can once again be made via anindication element, for example if the previous calibration quality isinsufficient and/or if this is an expedient time to carry out acalibration method.

In another alternative or in addition thereto, the calibration strategycan also comprise a method step in which a user is informed that this isan expedient time to carry out the calibration method. In particular,this information can once again be provided by an indication element. Asalready explained above, an expedient time can be present, inparticular, in the case when signal dynamics of the measurement signalsare currently low and/or in the case when a large deviation in theconcentration of the at least one analyte in the bodily fluid isexpected compared to previous analyte concentrations.

In another alternative or in addition thereto, the calibration strategycan also comprise a method step in which a user is invited to carry outthe calibration method or to carry it out again at regular or irregularintervals, e.g., at prescribed intervals. By way of example, such aninvitation may occur after a prescribed number of hours have elapsedsince the last time the calibration method was carried out.

In addition to the method according to one or more of the above-proposedembodiments, a computer program with program code for carrying out themethod according to one or more of the proposed variants when theprogram is executed on a computer is furthermore proposed. Inparticular, the computer program can be carried out on a computer of acontrol of the measuring equipment for detecting at least one analyte ina bodily fluid. The computer program can more particularly be stored ona computer-readable data medium.

In addition to the method and the computer program, measuring equipmentfor detecting at least one analyte in a bodily fluid is furthermoreproposed. The measuring equipment can in particular comprise at leastone continuously measuring sensor, more particularly a continuouslymeasuring blood glucose sensor. The measuring equipment is designed toproduce at least one measurement signal corresponding to a concentrationof the analyte in the bodily fluid. The measuring equipment isfurthermore designed to receive reference values detected by means of anindependent reference measurement. The measuring equipment has at leastone control, more particularly a control with at least one computer,wherein the control is designed to carry out a method according to oneor more of the above-described method variants. Here, the measuringequipment may comprise one or more components, which may be embodied ina connected or non-connected fashion. Thus, for example, the measuringequipment can comprise a plurality of individual items of measuringequipment, i.e., have a decentralized design, wherein the individualitems of measuring equipment interact within the meaning of themeasuring equipment according to the invention. By way of example, thesecould be the continuously measuring sensor and control equipment and/orfurther measuring equipment, which may be in communication with oneanother in a wired or wireless fashion. Accordingly, measuring equipmentcan also be understood to mean a measuring system with a plurality ofindividual components, preferably with a plurality of components thatare connected to one another via a communication link. However,alternatively, integration in a single item of measuring equipment isalso possible.

The proposed method, the computer program and the measuring equipment inone or more of the above-described embodiment variants have a number ofadvantages over known methods and devices of this type. Thus, inparticular, it is possible to achieve a stable calibration, which isalso comparatively insensitive in respect of outliers. In contrast tothe method described in US Publication No. 2006/0281985, for example, inwhich median calculations are only used for the measurement values,according to this disclosure, a regression is used directly for thecalibration method as per a first aspect of this disclosure. Theprobable slope established in the process reflects the sensitivity ofthe measuring equipment, e.g., of the measuring system. The method canbe implemented in a simple and quick fashion and is particularlysuitable for continuously measuring blood glucose measuring equipment,in which the above-described difficulties may occur during thecalibration.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned aspects of exemplary embodiments will become moreapparent and will be better understood by reference to the followingdescription of the embodiments taken in conjunction with theaccompanying drawings, wherein:

FIGS. 1A-1D show method steps of a first exemplary embodiment of amethod with a calibration method for determining a probable slope and,optionally, a probable axis intercept;

FIG. 2 shows an exemplary embodiment of carrying out plausibilityanalysis;

FIG. 3 shows a further exemplary embodiment of plausibility analysisusing a failsafe mechanism;

FIG. 4 shows a schematic flowchart of an exemplary embodiment of amethod according to the invention; and

FIG. 5 shows an exemplary embodiment of measuring equipment according tothe invention.

DETAILED DESCRIPTION

The embodiments described below are not intended to be exhaustive or tolimit the invention to the precise forms disclosed in the followingdetailed description. Rather, the embodiments are chosen and describedso that others skilled in the art may appreciate and understand theprinciples and practices of the present invention.

In the following text, FIGS. 1A to 5 should be used to illustrateexemplary embodiments of a method and of measuring equipment 110, fordetecting at least one analyte in a bodily fluid. FIG. 5 schematicallyillustrates an exemplary embodiment of such measuring equipment 110. Inthis case, the measuring equipment is measuring equipment for continuousblood glucose monitoring by means of a continuously measuring bloodglucose sensor 112. By way of example, this continuously measuringsensor can be implanted into interstitial tissue of a user and remainthere over a period of time of, e.g., a number of days. The measuringequipment 110 furthermore comprises a control 114 with at least onecomputer 116. Furthermore, the measuring equipment 110 can comprise oneor more indication elements and/or one or more operating elements, and,optionally, one or more interfaces for allowing interaction between themeasuring equipment 110 and a user and/or other equipment, e.g., acomputer or a computer network. As indicated by the reference sign 118in FIG. 5, the control 114 is connected to the continuously measuringblood glucose sensor 112 in a wireless or wired fashion.

Furthermore, the measuring equipment 110 is designed to receive one ormore independently detected reference values. This reception ofreference values is characterized by reference sign 120. In order toproduce the reference values, provision can be made for separatereference measuring equipment 122, for example test-strip measuringequipment for the spot measurement of blood glucose values in drops ofblood. Alternatively, or in addition thereto, the reference measuringequipment 122 can also be wholly or partly integrated into the measuringequipment 110 itself. This should also be encompassed by the phrasereceiving reference values.

FIGS. 1A to 1D illustrate an exemplary embodiment of a calibrationmethod for prospective calibration of the measuring equipment 110. An atleast approximately linear relationship between the measurement signalsfrom the measuring equipment and the reference values from referencemeasurements is assumed for the calibration method. Alternatively, inthe case of a nonlinear relationship, a linear relationship (i.e., alinear profile of the measurement value—concentration line) can beproduced by a fixedly prescribed, nonlinear transform, more particularlyas a preceding linearization step or linearization transform of themeasurement values or of the measurement signal, before these are or itis considered on the basis of the slopes. In particular, use can be madeof the above-described linearization transforms. The measurement signalsfrom the measuring equipment are denoted by I in FIGS. 1A-1D and are, inan exemplary fashion, specified in ampere. However, in principle, anyunits and/or variables may be used as measurement signals. Here, themeasurement signals I are plotted on the y-axis in FIGS. 1A-1D. Bycontrast, the reference values are denoted by c_(R) in FIGS. 1A-1D andare specified in arbitrary concentration units. By way of example, thesecan be reference values that were established by means of referencemeasuring equipment 122 in the form of handheld equipment, e.g.,analogously to FIG. 5. However, alternatively or in addition thereto,these reference values can also, as illustrated above, be established bythe measuring equipment 110 itself by means of a reference measuringmethod, for example by integrating such reference measuring equipment122 into the measuring equipment 110. The above-described linearrelationship between the measurement signals from the measuringequipment and the reference values is assumed to hold at least in ameasuring range, for example within a measuring range that is usuallynot undershot or overshot.

A goal of the calibration method is to determine the aforementionedrelationship. A linear relationship is defined by a slope a and an axisintercept b of a linear function with the functional equationI=a*c_(R)+b. In order subsequently to an analyte concentration c, e.g.,a blood glucose concentration, from a measurement signal from themeasuring equipment 110 during an actual measurement, the aforementionedlinear equation should be inverted, and so the equation c=(1/a)*I−b/acan be applied. Thus, the parameters a and b determine a calibration ofthe measuring equipment 110.

Thus, during prospective calibration, calibration points are determined,optionally iteratively, which calibration points respectively comprise ameasurement signal from the measuring equipment 110 and at least onereference value. The slope a and the axis intercept b are calculatedfrom these calibration points, for example according to the methoddescribed in the aforementioned publication by H. Passing and W. Bablok.

In order to ensure a quality of the parameter calculation that is ashigh as possible, the selection of the reference values is controlled bythe reference measuring equipment in a preferred embodiment. Inparticular, a reference value is not used for calibration (i.e.,excluded) if the associated signal from the measuring equipment has lowquality (large variation of the measurement values) or high dynamics(trend). By contrast, the user is invited to perform a calibration ifthe signal converted using the previously established calibrationparameters leaves the range covered by the already recorded calibrationvalues. This range or tolerance range can for example be given by theinterval [c_(lb):c_(ub)], with:c _(lb):=min{bG _(min) −Cp*d;bG _(min)*(1−d)} and c _(ub):=max{bG _(max)+Cp*d;bG _(max)*(1+d)}

Here, Cp is a prescribed, characteristic measurement point, d is aprescribed tolerance and bG_(min) and bG_(max) are the minimum andmaximum recorded reference value. The tolerance d used here is relativeand brings about a tolerance width determined by the respectivereference value. It is alternatively possible to determine the lowerboundary c_(lb) by the minimum reference value minus a prescribed,absolute tolerance-width value. If a measurement value occurs below theinterval, neither a measurement nor a display of the measurement resultis blocked. Instead, the measurement result is indicated and there is aninvitation to carry out the calibration or to repeat the measurement. Inparticular, this is carried out in cases in which a measurement valuecorresponds to a concentration that is typically considered to behypoglycemic (provided blood glucose is detected as an analyte). Thisprevents a hypoglycemic measurement from not being carried out or theresults thereof not being displayed because the calibration strategy inthis case (outside of the tolerance range, i.e., outside of thecalibrated range) necessarily requires a further calibration (cf. state(A)) before a measurement value is output.

FIG. 1A shows a first step, in which there merely is a singlecalibration point. By way of example, the origin can be assumed to be afurther calibration point. A straight line is defined by these twopoints, i.e., a measured calibration point and an assumed calibrationpoint, which may for example be the origin, wherein the slope and theaxis intercept (naturally equal to 0 if the origin is the selectedcalibration point) of this straight line can be determined.

Two calibration points, which define a straight line, are already knownin FIG. 1B. The slope a and axis intercept b of this straight line canlikewise be determined.

FIG. 1C illustrates the method if a multiplicity of calibration pointsare known; in this case n calibration points. Straight lines can then,as illustrated in FIG. 1C, be formed between all of these calibrationpoints or between a plurality of these calibration points, wherein theslopes a_(i) (with i=1, . . . n) of these straight lines can bedetermined. Thus, in the case of n calibration points, there are at mostn*(n−1)/2 possible slopes a.

In the proposed method, the median is then formed from all or at least aplurality of possible slopes a₁ to at most a_(n*(n-1)/2), which medianis referred to as probable slope a; for example, a=median{a₁, a₂, . . ., a_(n*(n-1)/2)}. However, alternatively or additionally, otheralgorithms could, for example, also be used in general, which algorithmsare based on one or more permutation algorithms and/or one or moresorting algorithms, from which the formation of a median merelyconstitutes a preferred example; this has already been illustratedabove. However, alternatively or additionally, use can in principle alsobe made of other robust estimation methods.

The probable slope a established thus can already be used in subsequentmeasurements, for example by using a straight line through the originwith the inverse of this slope for converting a measurement signal fromthe measuring equipment 110 into a blood glucose concentration. However,it is particularly preferred if an axis intercept b is additionally alsoestablished, the latter describing an offset. This is illustrated inFIG. 1D as an optional method step. In this method step, a straight linewith the probable slope is placed through each of the calibration pointsor at least through a plurality of the calibration points. The axisintercept b, of this straight line is determined, in particularcalculated according to the equation b_(i)=y_(i)−a*x_(i). Here x_(i) andy_(i) denote the reference measurement and the measurement signal of thei-th calibration point. Using this plurality of axis intercepts b₁, . .. , b_(n), i.e., a plurality or all of these axis intercepts, it is onceagain possible to determine a probable axis intercept b, for exampleaccording to the equation b=median{b₁, b₂, . . . , b_(n)} using anestimation method, preferably a robust estimation method, moreparticularly a robust estimation method using a median.

The linear relationship between the reference values and the measurementsignals is fully known using the probable slope a and the probable axisintercept b. In order to deduce a concentration of the analyte in thebodily fluid from a measurement signal in a following measurement, allthat needs to be done is to invert this linear relationship, for exampleaccording to the above-described equation c=(1/a)*I−(b/a).

The method, described using FIGS. 1A to 1D, with the calibration methodcan also be carried out repeatedly. In particular, the method can becarried out such that a regression as per the aforementioned publicationby H. Passing and W. Bablok is carried out with every newly addedcalibration point with a measurement value pair. In this respect,reference can for example be made to the aforementioned publication. Inconclusion, the method can thus for example be carried out as follows:

1. Start: If 2 calibration points or measurement pairs (e.g., continuousmeasurement current I, blood glucose reference value c_(R)) are present,a slope and the axis intercept are calculated.

2. If an additional calibration point in the form of a measurement pairis added, proceed as follows:

-   -   a. Calculate the additional slopes between the available pairs.    -   b. Form the median from a plurality of, preferably all, slopes        calculated thus (in the case of 3 pairs, there are 2*3/2=3        slopes; in the case of n points, there are n*(n−1)/2). This        median is used as new value for the probable slope of the        calibration straight line.    -   c. Place a straight line with the probable slope, calculated in        2b), against each calibration point.    -   d. Calculate the intersection with the y-axis (x=0) for a        plurality of points, preferably for every point.    -   e. Calculate the median of all axis intercepts calculated thus.        This is a new estimated value for the probable axis intercept of        the calibration straight line.

3. The calibration straight line calculated thus serves for convertingmeasurement signals into blood glucose values until a furthercalibration pair is available. Then go to 2.

By prescribing a reference point (e.g., an expected current value in thecase of a glucose concentration of 0 mg/dl), this method can inprinciple also implement a single-point calibration, as illustrated inFIG. 1A.

As a result of using robust median estimators, the method offers theadvantage of being robust against outliers and measurement errors. Inprinciple, an evaluation of the quality of the recorded calibrationpoint is no longer necessary, but it may optionally be carried outadditionally.

The method described above using FIGS. 1A-1D can be developed by variousembodiments. One option consists of applying a data compression,although the latter can, in principle, also be utilized independently.Such data compression can be used both in the calibration method whendetermining the calibration points and during the actual measurement inwhich an analyte concentration in the bodily fluid is deduced, or duringone of these method steps.

A first method for reducing the amount of data consists of forming amedian from a plurality of individual measurement signals. Thus, inorder to reduce the amount of data for calibration and/or forevaluation, there can be a compression of measurement signals, whichwere for example recorded in the sub-minute range, for example to valuesin the minute range. To this end, a plurality of measurement signals canbe recorded for the respective measurement time period. Here n specifiesthe number of utilized values in the sub-minute range. Then, e.g., themedian can be calculated from these values, i.e., the individualmeasurement signals of the measurement time period, and can be used ascompressed value for the respective value in the minute range. By way ofexample, this compressed measurement signal can then be used in thecalibration method and/or during the actual measurement. It is likewisepossible to calculate measures of variation, e.g., the standarddeviation and/or the measure of the quantile, in the time interval ofthe measurement time period. By way of example, the signal state can bederived from these measures of variation. In this respect, reference canfor example also be made to U.S. Pat. No. 7,389,133 B1 and USPublication No. 2007/0016127 A1. By making a comparison between therobust estimators, e.g., the median and/or the measures of the quantile,and parametric estimators, e.g., the mean and/or the standard deviation,it is likewise possible to make statements in respect of the signalquality.

A second method for data compression, which can be used alternatively oradditionally and, e.g., is once again in the minute range or based onanother measurement time period, can be carried out by renewedapplication of a regression method using one or more robust estimationmethods. By way of example, to this end, analogously to theaforementioned description of FIG. 1C, possible slopes between all or aplurality of the measurement signals of the measurement time period, forexample all or a plurality of slopes between respectively two values inthe sub-minute range, can be calculated from the plurality ofmeasurement signals in the measurement time period to be compressed, andthe median of all slopes can subsequently be determined. Straight lineswith this median slope, which once again constitutes an example of aprobable slope, can be placed through all or a plurality of current-timepoints in the measurement time period and in each case it is possible tocalculate or determine the value of this straight line at a specifictime, which is selected as representative time for the measurement timeperiod, e.g., the middle of the period of time. The median of allcurrent-time estimators calculated thus at the representative time, atwhich the evaluation is carried out, is the measurement value for thismeasurement time period. This principle is also referred to as repeatedmedian principle. The calculated slope of the straight line, i.e., theprobable slope, can moreover be considered as a measure of the trend forthis measurement time period.

In a further possible embodiment of the method, which should beexplained on the basis of FIG. 2, it is possible to assess thecalibration quality. Thus, for example, confidence intervals can becalculated to assess the current quality of the calibration. This makesit possible to estimate if and when a further calibration must becarried out, i.e., if and when the above-described calibration methodneeds to be carried out again. Furthermore, an estimation is madepossible as to whether the range (i.e., range or tolerance range), i.e.,the difference between the maximum value of the analyte concentrationand the minimum value of the analyte concentration, which is used tocarry out the calibration method, is sufficient for a reliablecalibration. It is also possible to restrict in advance the range of theslopes allowed for the calculation.

It is likewise possible to exclude old calibration points, the recordingtime of which lies further back than a fixedly prescribed time interval,from the calibration and thus compensate for a temporal change in thesystem because in this case a new calibration is invited or forced.

Thus, FIG. 2 plots a possible statistical distribution of theestablished slopes in a histogram 126. Here, the y-axis denotes thenumber N of counts of a specific slope, whereas the slope is plotted onthe x-axis. It is likewise possible to identify from FIG. 2 that a lowerthreshold 128 and/or an upper threshold 130 can be prescribed, withoutliers (denoted by reference sign 132 in FIG. 2, i.e., slopes outsideof the region prescribed by the thresholds 128, 130) being discarded,which can consist of these values being completely ignored or only beingprovided with a very low weighting. This makes it possible to avoid anerroneous calibration by restricting the range of admissible slopes fordetermining the median.

The data reduction is preferably executed with a constant reduction.Further, alternative embodiments provide for the calibration qualitymoreover being able to be included in one or both of the above-describedmethods for data reduction. Thus, for example, as illustrated above,there may be a data reduction of the measurement signals of ameasurement time period to one or a few representative measurement valuepairs, wherein each measurement value pair for example comprises ameasurement value and a time of the measurement. By way of example, asub-minute based amount of measurement points can respectively becompressed to a value in the minute range.

Here, this representative measurement value pair may be stored alone,wherein, for example, the representative measurement value pair cancomprise a representative measurement value or a representativemeasurement signal and a representative time of the measurement timeperiod. However, for the purpose of keeping information, for example inorder to carry out automatic fault avoidance (failsafe), additionalinformation may be added to this representative measurement value pair.By way of example, use can be made of a 5-dimensional vector in which,for each representative time of the measurement time period, a meanand/or a standard deviation and/or a 25%-quantile and/or a 75%-quantileare also stored in addition to the median.

As an alternative to the plausibility analysis described in FIG. 2, inwhich slopes outside of the range specified by the thresholds 128, 130are automatically rejected or discarded, or in addition thereto,provision can be made for further failsafe mechanisms. These canoptionally be used in the calibration method and/or during the actualmeasurement for determining the analyte concentration from themeasurement signals.

FIG. 3 illustrates a measurement of raw measurement signals over aperiod of time. Here, the individual points denote the actualmeasurement signals. Here, the x-axis represents the time t. Themeasurement signals I are plotted on the left y-axis in arbitrary units.The measurement signals are denoted by reference sign 134 in FIG. 3.FIG. 3 furthermore in each case plots—this is denoted by reference sign136—the median of the measurement signals 134 over one minute, whichmedian is represented as a step function.

FIG. 3 furthermore illustrates two difference curves, which emerge fromthe differences between various quantiles and the median 136. Thesedifferences are specified on the right y-axis in arbitrary units. Thedifference between the 0.25-quantile and the median 136 (reference sign138) and the difference between the 0.75-quantile and the median(reference sign 140) are shown. Within the scope of these teachings, aquantile of order p or a p-quantile generally specifies a value belowwhich a prescribed proportion p of all cases of the distribution lies.Each value below Qp undershoots this prescribed proportion. Here p canbe any real number between 0 and 1.

In order to obtain automatic fault avoidance, i.e., implement a failsafemethod, these differences 138, 140 can be examined using a thresholdingmethod. In the process, one or more thresholds 142, 144 can beprescribed, and the differences 138, 140 can be compared to thesethresholds 142, 144. Accordingly, e.g., all differences 138 that liebelow the lower threshold 142 can be discarded, as can all differences140 that lie above the upper threshold 144. By way of example, thismakes it possible to exclude, or provide very low weighting to, e.g.,values in the minute range with particularly high deviations. By way ofexample, this makes it possible to implement an automatic failsafemethod. However, care should preferably be taken in this case that thethresholds 142, 144 are not selected such that, e.g., values in theminute range are not spuriously removed during great changes, i.e., inthe case of steep slopes, caused by changes in the analyteconcentration.

A further aspect of the method according to this disclosure consists ofthe option of applying a calibration strategy. In principle, thiscalibration strategy can be used independently of the remaining aspectsof the proposed method; however, it is particularly advantageous incombination with all or some of the above-described embodiments of theproposed method. Thus, a calibration strategy may for example consist ofrestricting the analyte concentration range, e.g., the glucose range,that can be seen by the user depending on the quality of thecalibration. Thus, for example, outside of this range, a display can beswitched to “lower boundary undershot” or “upper boundary overshot.”Alternatively, or in addition thereto, the calibration strategy may alsoconsist of inviting the user to a renewed calibration. As anotheralternative, or in addition to the above, the calibration strategy mayalso consist of signaling to the user when an expedient calibration timeis present, i.e., an expedient time for carrying out the above-describedcalibration method and/or another calibration method. By way of example,an expedient calibration time may be present if there currently are lowdynamics in the measurement signals and/or if an analyte concentrationvalue to be expected deviates strongly from the previous values. Othertypes of expedient calibration times are also possible.

In a further aspect of this disclosure, it is possible to smooth rawvalues, for example by means of at least one exponential filter. By wayof example, this smoothing can be used to carry out the calibrationmethod and/or for the actual measurement in order to obtain smoothedmeasurement signals from the measurement signals. By way of example, usecan be made of an exponential filter as described in, e.g., Hartung:Statistik. Lehr- and Handbuch der Angewandten Statistik [Statistics.Textbook and handbook of applied statistics], 14^(th) edition, ChapterXII, 1.3.4.: Exponentielles Glatten [Exponential smoothing], p. 672-673.

In order to smooth the raw values of the measurement signals, use canfor example be made of a method in which x₁, . . . , x_(m) represent thevalues to be smoothed. Then the smoothed values {tilde over (x)}₁; . . .; {tilde over (x)}_(m) for example emerge from the followingprescription:

$\overset{\sim}{x_{1}} = \left\{ {{\begin{matrix}{x_{1},\mspace{20mu}{{{if}\mspace{14mu}{status}\mspace{20mu}\left( x_{1} \right)} = {valid}},} \\{0\mspace{20mu}{{otherwise}.}}\end{matrix}{and}\overset{\sim}{x_{n + 1}}} = \left\{ {{\begin{matrix}{{{\alpha\; x_{n + 1}} + {\left( {1 - \alpha} \right)\overset{\sim}{x_{n}}}},\mspace{14mu}{{{if}\mspace{14mu}{status}\mspace{14mu}\left( x_{n + 1} \right)} = {valid}},} \\\overset{\sim}{x_{n}\mspace{14mu}{{otherwise}.}}\end{matrix};{n = 1}},\ldots\mspace{11mu},{m - 1.}} \right.} \right.$

By way of example, the status of a value can be obtained by theabove-described plausibility method. Thus, for example, the status canbe set to invalid if one of the thresholds 142, 144 is respectivelyundershot or overshot in the plausibility method shown in FIG. 3. Thestatus is otherwise set to valid. By contrast, the value α denotes asmoothing factor, lying in the interval between 0 and 1. By way ofexample, for α=0 this constantly results in the initial value, whereasthere is no smoothing for α=1. The smoothing factor α can for example beset in a data storage device of the measuring equipment 110, for examplein a persistent data storage device. As already illustrated above, themeasuring equipment 110 can also have a decentralized design, and so ameasurement system with a plurality of individual components, e.g.,components connected by a unidirectional or bidirectional communicationlink, such as, e.g., continuously or discretely measuring sensors,control equipment, external storage devices or similar components canalso be included by the term measuring equipment 110.

Furthermore, it is also possible to carry out at least one linearizationstep, both in the above-described calibration method and during theactual measurement for establishing the analyte concentration, or inmerely one of the aforementioned method steps. By way of example, shouldit turn out that a current-analyte concentration relationship (or acorresponding ratio or function) is nonlinear (at least in sections), itis possible to carry out such a linearization step in an intermediatestep. Here, e.g., the raw measurement signals, e.g., the raw currentvalues, can be mapped by a linearization function such that theconverted measurement signals have a linear relationship with theanalyte concentration in the bodily fluid. This method lends itselfparticularly to a pre-calibration. By way of example, the correspondingconversion function can be determined batch-dependent at a measuringstand and can be stored in a data storage device of the control 114,e.g., once again in a persistent data storage device. The actual finecalibration can then be carried out in vivo, as described above.

FIG. 4 finally illustrates a possible schematic flowchart of anexemplary embodiment of a method for operating measuring equipment 110for detecting at least one analyte in a bodily fluid. Here, thereference sign 146 denotes the generation of one or more measurementsignals, in particular as a function of time. By way of example, currentmeasurement signals from the measuring equipment 110, more particularlyfrom the blood glucose sensor 112, can be recorded every second. Thesemeasurement signals can optionally be smoothed; this is indicated byreference sign 148 and may include filtering. By way of example, use canbe made here of an exponential filter, for example as per theabove-described function.

In method step 150 there may optionally be data compression, for exampleas per one or more of the above-described methods. By way of example,this can a “downsizing” of measurement values recorded in the sub-minuterange to values in the minute range.

Subsequently there may optionally be plausibility analysis in methodstep 152, in particular within the scope of a so-called failsafe method.In the process, as described above on the basis of FIG. 3 for example,implausible measurement signals may be discarded.

Subsequently, in method step 154, there can optionally be a transmissionof the measurement signals processed thus. By way of example, there maybe a transmission to the control 114 and/or a data storage device of thecontrol 114 or a further-processing computational unit.

Subsequently there can be another optional smoothing in method step 156,for example there can once again be filtering.

Calibration points are formed in method step 158, in which referencevalues of associated reference measurements are assigned tocorresponding measurement signals or the processed measurements signals(e.g., optionally smoothed and/or compressed measurement signals and/ormeasurement signals evaluated in any other way). This method step 158can also be referred to as synchronization.

Subsequently, in method step 160, it is possible to carry out thecalibration method for prospective calibration of the calibrationpoints. As described above, for example, a relationship is produced inthis calibration method between the measurement signals, i.e.,optionally the processed measurement signals, and the analyteconcentration in the bodily fluid. By way of example, as describedabove, this can be carried out by way of establishing the at least oneprobable slope and, optionally, the at least one probable axisintercept. This established relationship can subsequently be used for ameasurement in, e.g., the measuring equipment 110 in order to determinethe analyte concentration from the measurement signals. Said analyteconcentration can for example be indicated on a display 162 of themeasuring equipment 110.

As illustrated above, the method can optionally comprise a calibrationstrategy. By way of example, this calibration strategy may comprise arecommendation to carry out a calibration method. This is denoted byreference sign 164 in FIG. 4. By way of example, this recommendation canin turn be indicated on a display 162 of the measuring equipment 110. Inparticular, use can be made of a calibration strategy as described aboveon the basis of states (A)-(E).

While a relationship between the measurement signals and the analyteconcentration is established for future measurements during theprospective calibration of the measuring equipment 110, there canoptionally also be a retrospective calibration. This is denoted byreference sign 166 in FIG. 4. In the retrospective calibration, use canfor example be made of calibration information added in the meantime inorder to reevaluate older measurement signals, which additionalcalibration may have for example led to a more precise and less reliablecalibration. By way of example, this may take place on the measuringequipment itself and/or, as illustrated in FIG. 4, on a furthercomputer, e.g., a computer of a medical practitioner 168. This makes itsubsequently possible to evaluate measurements with a greater accuracy.

While exemplary embodiments incorporating the principles of the presentinvention have been disclosed hereinabove, the present invention is notlimited to the disclosed embodiments. Instead, this application isintended to cover any variations, uses, or adaptations of the inventionusing its general principles. Further, this application is intended tocover such departures from the present disclosure as come within knownor customary practice in the art to which this invention pertains andwhich fall within the limits of the appended claims.

LIST OF REFERENCE NUMERALS

-   110 Measuring equipment for detecting an analyte in a bodily fluid-   112 Continuously measuring blood glucose sensor-   114 Control-   116 Computer-   118 Connection-   120 Reception of reference values-   122 Reference measuring equipment-   126 Histogram of the slopes-   128 Lower threshold-   130 Upper threshold-   132 Outlier-   134 Measurement signals-   136 Median of the measurement signals-   138 Difference between 25th quantile and the median-   140 Difference between 75th quantile and the median-   142 Lower threshold-   144 Upper threshold-   146 Generating measurement signal-   148 Smoothing-   150 Data compression-   152 Plausibility analysis-   154 Transmission-   156 Smoothing-   158 Forming calibration points-   160 Calibration method-   162 Display-   164 Recommendation to carry out the calibration method-   166 Retrospective calibration-   168 Computer of a medical practitioner

What is claimed is:
 1. A method for operating measuring equipment fordetecting at least one analyte in a bodily fluid, the measuringequipment including a continuously monitoring sensor and a referencemeasurement sensor, the method comprising: implanting the continuouslymonitoring sensor into the skin of a patient; detecting at least threecalibration points, each calibration point comprising (i) a measurementsignal obtained from the implanted sensor and corresponding to theconcentration of the analyte in the bodily fluid and (ii) a referencevalue obtained using the reference measurement sensor, wherein thereference value corresponds to an actual present value of concentrationof the analyte in the bodily fluid; establishing a plurality of possibleslopes between the calibration points; using a robust estimation methodto determine a probable slope from the plurality of possible slopes, therobust estimation method comprising a statistical estimation methodwhich supplies stable statistical estimators even if outliers occur orif distribution assumptions are only approximately valid, the robustestimation being based on one or more permutation algorithms and/or onone or more sorting algorithms; determining through a plurality of thecalibration points a plurality of straight lines having the probableslope; and using the continuously monitoring sensor to perform at leastone measurement in which the probable slope is used with the measurementequipment to determine a concentration of the analyte in the bodilyfluid.
 2. The method of claim 1, further comprising: determining theaxis intercepts of the straight lines; forming a median to determine aprobable axis intercept from the axis intercepts; and using the probableaxis intercept during the measurement.
 3. The method of claim 2, whereinthe calibration method is carried out repeatedly at different times, themethod further comprising determining a new probable slope and a newprobable axis intercept after the calibration method has been repeatedand then using the new probable slope and the new probable axisintercept in at least one subsequent measurement.
 4. The method of claim1, further comprising preforming plausibility analysis during thecalibration and using the plausibility analysis to discard unrealisticcalibration points and/or unrealistic slopes and/or unrealistic axisintercepts.
 5. The method of claim 1, further comprising using a sortingalgorithm and/or a permutation algorithm during the robust estimation toform a median.
 6. The method of claim 1, further comprising determiningat least one current calibration quality having at least one confidenceinterval.
 7. The method of claim 1, further comprising automaticallyinviting a user to carry out the calibration method.
 8. The method ofclaim 1, wherein a user is invited to carry out the calibration methodif at least one current measurement signal lies in a region in which thecalibration method was not yet carried out with sufficient calibrationquality.
 9. The method of claim 1, further comprising informing a userif a current measurement signal lies in a region of insufficientcalibration quality.
 10. The method of claim 1, further comprisingdiscarding at regular or irregular intervals calibration points that areolder than a predetermined time threshold.
 11. The method of claim 1,wherein the calibration points and/or the measurement signals aresubjected to at least one smoothing method, using an exponential filter.12. The method of claim 1, wherein the calibration points and/or themeasurement signals are subjected to at least one linearization step,wherein the linearization step produces an approximately linearrelationship between the measurement signals and the reference values.13. The method of claim 1, further comprising detecting a plurality ofthe measurement signals from the measuring equipment over a measurementtime period and applying a first data reduction method, comprising:combining the measurement signals with associated measurement times toform measurement value pairs, wherein a plurality of possible slopes areestablished between the measurement value pairs; using a median toestablish a probable slope from the plurality of possible slopes,wherein a plurality of straight lines with the probable slope throughthe measurement value pairs are formed; selecting a representative timefor the measurement time period and establishing functional values ofthe straight lines for the representative time; establishing a probablefunctional value from the functional values; and using the at least oneprobable functional value and the at least one representative time toreplace the plurality of the measurement value pairs with arepresentative measurement value pair; the method further comprisingapplying a second data reduction method, comprising: forming a medianand using the median to determine at least one probable measurementsignal for the measurement time from the plurality of measurementsignals, wherein the plurality of measurement signals are replaced bythe probable measurement signal.
 14. The method of claim 13, furthercomprising determining a standard deviation and/or a measure of thequantile.
 15. The method of claim 13, further comprising comparingrobust estimators of the measurement signals and parametric estimatorsof the measurement signals.
 16. The method of claim 13, furthercomprising determining a trend from the plurality of measurementsignals.
 17. The method of claim 1, wherein, during the calibrationmethod, a calibration of measurement signals from the measuringequipment is carried out against reference values of associatedreference measurements and the calibration strategy comprises one ormore of the following steps: a region of measurement signals from themeasuring equipment that can be used for a measurement is restricteddepending on a current calibration quality, wherein information isprovided to a user when detecting measurement signals outside of theregion that is usable or covered by calibration values or outside of atolerance region based on the calibration values; a user is invited tocarry out the calibration method again; a user is informed that now is agood time for carrying out the calibration method; and a user is invitedto carry out the calibration method again at regular or irregularintervals or at predetermined times.
 18. Measuring equipment fordetecting at least one analyte in a bodily fluid, comprising: acontinuously measuring bodily fluid analyte sensor adapted forimplanting into the skin of a patient; a processor having a programstored in memory and configured for execution by the processor, theprogram including instructions for: detecting at least three calibrationpoints, each calibration point comprising (i) a measurement signalobtained from the continuously measuring sensor implanted in a patient,the measurement signal corresponding to the concentration of the analytein the bodily fluid and (ii) a reference value obtained using areference measurement sensor, wherein the reference value corresponds toan actual present value of concentration of the analyte in the bodilyfluid; establishing a plurality of possible slopes between thecalibration points; using a robust estimation method to determine aprobable slope from the plurality of possible slopes, the robustestimation method comprising a statistical estimation method whichsupplies stable statistical estimators even if outliers occur or ifdistribution assumptions are only approximately valid, the robustestimation being based on one or more permutation algorithms and/or onone or more sorting algorithms; determining through a plurality of thecalibration points a plurality of straight lines having the probableslope; and using the implanted sensor to perform at least onemeasurement in which the probable slope is used with the measurementequipment to determine a concentration of the analyte in the bodilyfluid.
 19. The measuring equipment of claim 18, wherein the bodily fluidanalyte sensor comprises a glucose sensor.
 20. A method for operatingmeasuring equipment for measuring concentration of an analyte in abodily fluid, the measuring equipment including a continuouslymonitoring sensor, a reference measurement sensor, and a user interface,the method comprising: implanting the continuously monitoring sensorinto the skin of a patient; initially calibrating the continuouslymonitoring sensor using measurement signals obtained from the implantedsensor that are matched to respective reference values obtained with thereference measurement sensor; using the calibrated sensor tocontinuously monitor the concentration of the analyte in the patient'sbodily fluid; when a signal monitored from the calibrated sensor fallswithin a region that has less than a minimum number of calibrationpoints, the user interface generates a visual, audible or haptic signalto the patient to recalibrate the continuously monitoring sensor; andrecalibrating the sensor based on the visual, audible or haptic signal.21. The method of claim 20, wherein the user interface invites thepatient to recalibrate when the continuously monitoring sensor records avalue that exceeds or falls below all previously recorded values. 22.The method of claim 20, wherein the user interface informs the patientthat analyte measurement is terminated or interrupted and thecontinuously monitoring sensor suspends operation.
 23. The method ofclaim 20, wherein the step of the user interface inviting the patient torecalibrate comprises producing a “must calibrate” signal.
 24. Themethod of claim 20, wherein the step of the user interface inviting thepatient to recalibrate comprises producing a “calibration recommended”signal.
 25. The method of claim 20, wherein the step of the userinterface inviting the patient to recalibrate comprises producing a “maycalibrate” or “ready to calibrate” signal.
 26. The method of claim 20,wherein: the measuring equipment distinguishes between and selects oneof the following states: (a) mandatory calibration, wherein a display ofmeasurements is blocked until the measuring equipment is calibrated, and(b) recommended calibration, wherein the measuring equipment continuesto display measurement results if the user does not calibrate; and theuser interface displays the selected state.
 27. The method of claim 20,wherein the minimum number of calibration points is at least
 3. 28. Themethod of claim 20, wherein the minimum number of calibration points isat least 2.